14 Hemostasis Disorders

Normal Hemostasis and Hemostasis Testing

Prevention of blood loss while maintaining maximal perfusion requires the interaction of the
blood vessels, platelets, coagulation factors, and fibrinolytic agents.
Normal
Hemostasis
and
Hemostasis
Testing
Prevention of blood loss while maintaining maximal perfusion requires the interaction of the
blood vessels, platelets, coagulation factors, and fibrinolytic agents.
Normal anticoagulation in small blood vessels
Small blood vessels include capillaries, venules, arterioles.
1. Heparinli!e molecules
a. "nhance antithrombin ### $%&###' activity
b. Neutrali(e serine protease coagulation factors
)actors *##, *#, #*, and *+ prothrombin $factor ##'+ and thrombin
,. Prostaglandin $P-' #, $prostacyclin'
a. Synthesi(ed by intact endothelial cells
b. P-H, is converted by prostacyclin synthase to P-#,.
c. .asodilator and inhibits platelet aggregation
d. %spirin does not inhibit synthesis of P-#, by endothelial cells.
/. Protein 0 and S
a. .itamin 1dependent factors
b. #nactivate factors . and .###
c. "nhance fibrinolysis
2. &issue plasminogen activator $tP%'
a. Synthesi(ed by endothelial cells
b. %ctivates plasminogen to release plasmin
c. Plasmin degrades coagulation factors and lyses fibrin clots $thrombi'.
Procoagulants released in small vessel in3ury
page ,45
page ,46
)actor .###70 is synthesi(ed in the liver. 8hen .###70 is activated by thrombin, it
dissociates from the .###7v8) complex and performs its procoagulant function in
the intrinsic coagulation cascade system.
1. &hromboxane %, $&*%,'
a. Synthesi(ed by platelets
i. P-H, is converted into &*%, by thromboxane synthase.
ii. %spirin irreversibly inhibits platelet cyclooxygenase.
Prevents formation of P-H,, the precursor for &*%,
iii. 9ther nonsteroidal antiinflammatory drugs reversibly inhibit platelet
cyclooxygenase.
b. )unctions of &*%, in hemostasis
.asoconstrictor, enhances platelet aggregation
22 .on 8illebrand factor $v8)'
a. Synthesi(ed by endothelial cells and mega!aryocytes
i. Synthesi(ed in 8eibelPalade bodies in endothelial cells
ii. Platelets carry v8) in their :granules.
b. )unctions of v8)
i. Platelet adhesion molecule
;inds platelets to exposed collagen
Platelets have glycoprotein $-p'#b receptors for v8).
ii. 0omplexes with factor .###70 in the circulation
.###7v8) complexes prevent degradation of factor .###70
$procoagulant factor'.
<ecrease in v8) secondarily decreases .###70 activity.
,. &issue thromboplastin $factor ###'
c. Noncirculating ubiquitous substance
=eleased from in3ured tissue
b. %ctivates factor .## in the extrinsic coagulation system
22 "xtrinsic and intrinsic coagulation systems $see below'
Platelet structure and function
page ,46
page ,4>
1. <erivation
a. 0ytoplasmic fragmentation of mega!aryocytes
b. %pproximately 1??? to /??? platelets are produced per mega!aryocyte.
,. @ocations
a. Peripheral blood $live for >1? days'
b. %pproximately one third of the total platelet pool is stored in the spleen.
/. Platelet receptors
a. -lycoprotein receptors for v8) are designated -p#b.
b. -lycoprotein receptors for fibrinogen are designated -p##b7###a.
i. &iclopidine and clopidogrel
#nhibit %<Pinduced expression of platelet -p##b7###a receptors
Prevent fibrinogen binding and platelet aggregation
ii. %bciximab
Aonoclonal antibody that is directed against the -p##b7###a receptor
2. Platelet factor / $P)/'
a. @ocated on the platelet membrane
b. Phospholipid substrate required for the clotting sequence
4. Platelet structure
a. 0ontractile element
i. 0alled thrombosthenin
ii. Helps in clot retraction
b. <ense bodies contain7
i. %denosine diphosphate $%<P', an aggregating agent
ii. 0alcium, a binding agent for vitamin 1dependent factors
c. :-ranules contain7
i. v8), fibrinogen
ii. Platelet factor 2 $P)2'
Heparin neutrali(ing factor
B. Platelet function
a. )ill gaps between endothelial cells in small vessels
i. Prevents lea!age of =;0s into the interstitium
ii. Platelet dysfunction causes lea!age of =;0s, producing petechia.
b. )ormation of the hemostatic plug in small vessel in3ury
c. Plateletderived growth factor stimulates smooth muscle hyperplasia.
#mportant in the pathogenesis of atherosclerosis
0oagulation system
page ,B?
8arfarin is an anticoagulant that inhibits epoxide reductase, which prevents any
further Ccarboxylation of the vitamin 1dependent coagulation factors.
However, full anticoagulation does not immediately occur, because previously C
carboxylated factors are still present. Prothrombin has the longest halflife+
therefore, full anticoagulation requires at least / to 2 days before all functional
prothrombin has disappeared. &his explains why patients are initially placed on
both heparin and warfarin, because heparin immediately anticoagulates the
patient by enhancing %&### activity.
page ,B?
page ,B1
8hen blood is drawn into a clot tube $no anticoagulant is added', a fibrin clot is
formed. 8hen the tube is spun down in a centrifuge, the supranate is called
serum, which, unli!e plasma, is missing fibrinogen, prothrombin $##', factor .,
and factor .###.
1. 0oagulation cascade
a. "xtrinsic system $factor .##'
b. #ntrinsic system $factors *##, *#, #*, .###'
,. "xtrinsic system
a. )actor .## is activated $factor .##a' by tissue thromboplastin.
b. )actor .##a activates factor * in the final common pathway.
/. #ntrinsic system
a. )actor *## $Hageman factor' is activated by7
i. "xposed subendothelial collagen
ii. Highmolecularweight !ininogen $HA81'
b. )unctions of factor *##a
i. %ctivates factor *#
ii. %ctivates plasminogen $produces plasmin'
iii. %ctivates the !ininogen system $produces !alli!rein and brady!inin'
c. )actor *#a activates factor #* to form factor #*a
i. )ourcomponent complex is formed $#*a, .###, platelet factor /, calcium'
ii. 0omplex activates factor * in the final common pathway.
iii. 0alcium binds factor #*a, a vitamin 1dependent coagulation factor.
2. )inal common pathway
a. #ncludes factors *, ., prothrombin $##', and fibrinogen $#'
b. Prothrombin complex
i. )ourcomponent system consisting of factor *a, factor ., platelet factor /,
and calcium
ii. 0alcium binds factor *a, a vitamin 1dependent coagulation factor.
iii. 0omplex cleaves prothrombin into thrombin $en(yme'.
c. )unctions of thrombin
i. %cts on fibrinogen to produce fibrin monomers plus fibrinopeptides % and ;
ii. %ctivates fibrin stabili(ing factor *###
)actor *###a converts soluble fibrin monomers to insoluble fibrin.
"nhances proteinprotein crosslin!ing to strengthen the fibrin clot
iii. %ctivates .###70 in the intrinsic system
4. .itamin 1dependent factors
a. )actors ##, .##, #*, *, protein 0, and protein S
b. Synthesi(ed in the liver as nonfunctional precursor proteins
c. )unction of vitamin 1
i. .itamin 1 is activated in the liver by epoxide reductase.
Aa3ority of vitamin 1 is synthesi(ed by colonic bacteria.
ii. %ctivated vitamin 1 Ccarboxylates each factor.
0arboxylated factors can bind to calcium and P)/ in the cascade
sequence.
B. 0ertain coagulation factors are consumed in the formation of a fibrin clot.
o 0onsumed factors are fibrinogen $#', factor ., factor .###, and prothrombin $##'
)ibrinolytic system
1. %ctivation
a. tP% activates plasminogen to release the en(yme plasmin.
%lteplase and reteplase are recombinant forms of tP% used in thrombolytic
therapy.
b. 9ther activators of plasminogen
22 )actor *##a
222 Strepto!inase $derived from streptococci'
2222 %nistreplase $complex of strepto!inase and plasminogen'
2v2 Dro!inase $derived from human urine'
b. %minocaproic acid
0ompetitively bloc!s plasminogen activation, thereby inhibiting fibrinolysis
22 )unctions of plasmin
a. 0leaves insoluble fibrin monomers and fibrinogen into fibrin$ogen' degradation
products $)<Ps'
)ragments of crosslin!ed insoluble fibrin monomers are called <dimers.
b. <egrades factors . and .###
c. :,%ntiplasmin $synthesi(ed in the liver' inactivates plasmin.
Small vessel hemostasis response to in3ury
page ,B,
1. Sequence involves vascular, platelet, coagulation, and fibrinolytic phases.
,. .ascular phase
a. &ransient vasoconstriction occurs directly after in3ury.
b. )actor .## $extrinsic system' is activated by tissue thromboplastin.
c. "xposed collagen activates factor *## $intrinsic system'.
/. Platelet phase
a. Platelet adhesion
Platelet -p#b receptors adhere to exposed v8) in damaged endothelial
cells.
b. Platelet release reaction
=elease of adenosine diphosphate $%<P' causes platelet aggregation in the
lumens of in3ured vessels.
c. Platelet synthesis and release of &*%,
22 .essels constrict $reduce blood flow'.
222 Platelet aggregation is further enhanced.
b. &emporary platelet plug stops bleeding.
22 %ggregated platelets have fibrinogen attached to their -p##b###a receptors.
222 #t is an unstable plug that can easily be dislodged.
,. 0oagulation phase
a. &hrombin is produced by locali(ed activation of the coagulation cascade.
9ccurs in the vascular phase
b. )ibrinogen attached to -p##bE###a receptors is converted to insoluble fibrin
monomers.
c. Stable platelet plug is formed.
22 )ibrinolytic phase
a. Plasmin cleaves the insoluble fibrin monomers holding the platelet plug together.
b. ;lood flow is reestablished.
Platelet tests
Table 14-1. Causes of Prolonged Bleeding Time
Cause Nature of Defect Comments
%spirin or NS%#<s Platelet aggregation defect
#nhibition of platelet 09*, which ultimately
inhibits synthesis of &*%,
Normal platelet count
;ernardSoulier
syndrome
Platelet adhesion defect
%utosomal recessive disease
%bsent -p#b platelet receptors for v8)
&hrombocytopenia, giant platelets
@ifelong bleeding problem
-lan(mannFs disease Platelet aggregation defect
%utosomal recessive disease
%bsent -p##b###a fibrinogen receptors
@ifelong bleeding problem
%bsent thrombosthenin
=enal failure Platelet aggregation defect
#nhibition of platelet phospholipid by toxic
products
=eversed with dialysis and desmopressin
acetate
Scurvy .ascular defect
0aused by vitamin 0 deficiency
<efective collagen resulting from poor cross
lin!ing
Aay cause ecchymoses and hemarthroses
&hrombocytopenia <ecreased platelet number #ncreased bleeding time when platelet
count G>?,??? cellsEH@
.on 8illebrand
disease
Platelet adhesion defect
%utosomal dominant disorder
%bsent or defective v8)
<ecreased .###70
0ombined platelet and coagulation factor
disorder
09*, cyclooxygenase+ NS%#<, nonsteroidal antiinflammatory drug+ &*%,, thromboxane %,+ v8), von 8illebrand factor.
page ,B,
page ,B/
1. Platelet count
a. Normal count is 14?,??? to 2??,??? cellsEH@.
b. % normal count does not guarantee normal platelet function.
,. ;leeding time
a. "valuates platelet function up to the formation of the temporary platelet plug
Normal reference interval is , to 5 minutes.
b. <isorders causing a prolonged bleeding time are listed in
/. Platelet aggregation test
a. "valuates platelet aggregation in response to aggregating reagents
b. %ggregating agents include %<P, epinephrine, collagen, and ristocetin.
2. &ests for v8)
a. =istocetin cofactor assay
22 "valuates v8) function
222 %bnormal assay
0lassic von 8illebrand disease $deficiency of v8)'
;ernardSoulier disease $absent -p#b receptor'
b. v8) antigen assay
22 Aeasures the quantity of v8) regardless of function
222 <ecreased in classic von 8illebrand disease
0oagulation tests
page ,B2
8hether the patient is anticoagulated with heparin or warfarin, both the P& and
P&& are prolonged, because both inhibit factors in the final common pathway.
"xperience has shown that the P& performs better in monitoring warfarin, while
the P&& performs better in monitoring heparin.
1. Prothrombin time $P&'
a. "valuates the extrinsic system down to formation of the fibrin clot
)actors evaluated include .##, *, ., ##, and #
b. Normal reference interval for P& is 11 to 14 seconds.
9nly prolonged when a factor level is /?I to 2?I of normal
c. #nternational normali(ed ratio $#N='
22 Standardi(es the P& for use in warfarin therapy
222 =esults are the same regardless of the reagents used to perform the test.
b. Dses of P&
22 )ollow patients who are ta!ing warfarin for anticoagulation
222 "valuate liver synthetic function
#ncreased P& indicates severe liver dysfunction.
2222 <etect factor .## deficiency
,. Partial thromboplastin time $P&&'
a. "valuates the intrinsic system down to formation of a fibrin clot
)actors evaluated include *##, *#, #*, .###, *, ., ##, and #.
b. Normal reference interval for P&& is ,4 to 2? seconds.
9nly prolonged when a factor level is /?I to 2?I of normal
c. Dses of P&&
22 )ollow heparin therapy
Heparin enhances %&### activity.
P&& is not required to follow lowmolecularweight heparin therapy.
222 <etect factor deficiencies in the intrinsic system
)ibrinolytic system tests
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page ,B4
1. )ibrin$ogen' degradation products $)<Ps'
o <etects fragments associated with plasmin degradation of fibrinogen or insoluble
fibrin in fibrin clots
,. <<imer assay
a. 9nly detects crosslin!ed insoluble fibrin monomers in a fibrin clot
b. <oes not detect fibrinogen degradation products $not crosslin!ed'
c. Aost specific test for evidence of degradation of a fibrin clot $thrombus'+ examples7
i. &hrombolytic therapy for coronary artery thrombosis
&hrombus is composed of platelets held together by fibrin
ii. Screening test for pulmonary thromboembolism
&hrombus is composed of =;0s, platelets, white blood cells
$8;0s' held together by fibrin
iii. Screening test for disseminated intravascular coagulation $<#0'
&hrombus is composed of =;0s, platelets, and 8;0s held
together by fibrin $see Section ###'.
Platelet Disorders
0lassification of platelet disorders
1. Juantitative platelet disorders
a. &hrombocytopenia
b. &hrombocytosis
,. Jualitative $functional' platelet disorders
0lassification of platelet disorders
1. Juantitative platelet disorders
a. &hrombocytopenia
b. &hrombocytosis
,. Jualitative $functional' platelet disorders
Pathogenesis
Table 14-2. Disorders Producing Thrombocytoenia
Disorder Pathogenesis Comments
%cute idiopathic
thrombocytopenic
purpura $#&P'
#g- antibodies directed against -p##b7###a
receptors $type ## hypersensitivity reaction'
Aacrophages phagocytose platelets
Aost common childhood cause of
thrombocytopenia
%brupt onset after an upper respiratory tract
infection
%bsence of lymphadenopathy and
splenomegaly
=esponds to corticosteroids
0hronic idiopathic
thrombocytopenic
purpura
#g- antibodies directed against -p##b7###a
receptors $type ## hypersensitivity reaction'
Aost common cause of thrombocytopenia in
adults
Newborn infants may have transient
thrombocytopenia due to transplacental
passage of #g- antibodies
Secondary causes7 S@", H#.
Heparininduced
thrombocytopenia
&ype ## variant7 macrophage removal of
platelets surfaced by #g- antibody
directed against heparin attached to P)2
$type ## hypersensitivity'
9ccurs 412 days after heparin treatment
Aust discontinue heparin
=elease of P)2 after platelet destruction may
cause vessel thrombosis
H#. thrombocytopenia Similar to #&P Aost common hematologic abnormality in
H#. $not %#<Sdefining condition'
&hrombotic
thrombocytopenic
purpura $&&P'
%cquired or genetic deficiency in v8)
cleaving metalloprotease in endothelial
cells
"xcess of v8) increases platelet
adhesion to areas of endothelial in3ury at
arteriolecapillary 3unctions
Platelets consumed in the formation of
thrombi causes thrombocytopenia
"nhanced by factors that damage
endothelial cells $e.g., ticlopidine,
hypertension'
9ccurs in adult females
0linical pentad7 fever, thrombocytopenia,
renal failure, microangiopathic hemolytic
anemia with schistocytes $damage by platelet
thrombi', 0NS deficits
&reated with plasmapheresis
Aortality rate is 1?,?I
Hemolytic uremic
syndrome $HDS'
"ndothelial damage at arteriolecapillary
3unction caused by Shigali!e toxin of
?1457H5 serotype of Escherichia coli
9rganisms proliferate in undercoo!ed
Primarily occurs in children
0linical findings similar to &&P
0NS findings are less frequent
Aortality rate /4I
beef
0NS, central nervous system+ <#0, disseminated intravascular coagulation+ P)2, platelet factor 2+ S@", systemic lupus
erythematosus+ v8), von 8illebrand factor.
1. &hrombocytopenia
o <ecreased number of platelets
a. <ecreased production
"xamplesaplastic anemia, leu!emia
b. #ncreased destruction
22 #mmune
"xamplesidiopathic thrombocytopenic purpura, drugs
222 Nonimmune
"xamplesthrombotic thrombocytopenic purpura, <#0
b. Sequestration in the spleen
Hypersplenism in portal hypertension
,. &hrombocytosis
o #ncreased platelet count
o Primary thrombocytosis
"xamplesessential thrombocythemia, polycythemia vera
o Secondary $reactive' thrombocytosis
"xampleschronic iron deficiency, infections, splenectomy, malignancy
,. Jualitative platelet disorders
o %cquired $e.g., aspirin' or hereditary $e.g., -lan(mannFs disease'
0linical findings associated with platelet dysfunction
"cchymoses $purpura' can be caused by a variety of disorders unrelated to
platelet dysfunction. Palpable purpura $purpura that can be felt' is a sign of a
small vessel vasculitis . ;ecause vasculitis is a type of acute inflammation, the
lesions are palpable due to increased vessel permeability and not a platelet
disorder. Senile purpura is a normal finding in elderly patients and is due to
vessel instability . "cchymoses develop in areas of trauma $e.g., bac! of the
hands, shins'.
1. "pistaxis $nosebleeds' is the most common symptom.
,. Petechia and multiple small ecchymoses $purpura'
a. Petechia are pinpoint areas of hemorrhage in subcutaneous tissue .
=;0s lea! through gaps in the endothelium of venules and capillaries.
b. "cchymoses are the si(e of a quarter.
/. ;leeding from superficial scratches
o No temporary platelet plug is present to stop bleeding from in3ury to small vessels.
2. 9ther findings
a. Aenorrhagia, hematuria
b. ;leeding from tooth extraction sites
c. -astrointestinal and intracranial bleeding
Coagulation Disorders
0lassification of coagulation disorders
1. %cquired
o Single or multiple coagulation factor deficiencies
,. Hereditary
o Dsually a single coagulation factor deficiency
0lassification of coagulation disorders
1. %cquired
o Single or multiple coagulation factor deficiencies
,. Hereditary
o Dsually a single coagulation factor deficiency
Pathogenesis
page ,B5
page ,B6
1. <ecreased production
o "xampleshemophilia %, cirrhosis
,. Pathologic inhibition
o "xampleacquired circulating antibodies $inhibitors' against coagulation factors
/. "xcessive consumption
o "xampledisseminated intravascular coagulation
0linical findings in coagulation disorders
1. @ate rebleeding after surgery or wisdom tooth extraction
a. &emporary platelet plug is the only mechanical bloc! preventing bleeding.
b. @ac! of thrombin prevents formation of a stable platelet plug held together by fibrin.
,. )indings in severe factor deficiencies
a. Hemarthroses
b. =etroperitoneal and deep muscular bleeding
/. )indings similar to platelet disorders
a. "cchymoses, epistaxis
b. Aenorrhagia, hematuria
c. ;leeding from tooth extraction sites
d. -astrointestinal and intracranial bleeding
Hemophilia %
page ,B6
page ,B>
Hemophilia ; $0hristmas disease' is an *lin!ed recessive disorder involving a
deficiency of factor #*. #t is clinically indistinguishable from hemophilia %.
1. "pidemiology
a. *lin!ed recessive
i. )emales are asymptomatic carriers.
ii. )emales transmit the abnormal * chromosome to 4?I of their sons.
b. %bsent family history of hemophilia
Aost li!ely due to a new mutation $/?I of cases'
b. )emale carriers with symptomatic disease
i. <ue to inactivation of more maternal than paternal * chromosomes
ii. )emales become Khomo(ygousK for the abnormal * chromosome
,. Pathogenesis
o <ecreased synthesis of factor .###70 in the intrinsic system
2. 0linical findings in hemophilia %
a. Signs and symptoms correlate with the level of factor .###70 activity
i. %ctivity below 1I correlates with severe disease $e.g., spontaneous
hemarthroses'.
b. ;leeding problems may occur in newborns $1?14I of cases'.
i. "xcessive bleeding may occur after circumcision or umbilical cord
separation.
c. @aboratory findings in hemophilia %
i. #ncreased P&& and a normal P&
ii. <ecreased factor .###70 activity
iii. <ecreased factor .###7antigen $.###7%g'
)actor .### protein
iv. <etection of female carriers
<N% techniques are most sensitive.
2. &reatment of hemophilia %
a. Aild cases respond to desmopressin acetate
i. #ncreases .###70 activity
b. Severe cases require infusion of recombinant factor .###
i. No ris! for H#.
0lassic von 8illebrand disease $v8<'
1. "pidemiology
a. %utosomal dominant disorder
b. Aost common hereditary coagulation disorder
,. Pathogenesis
o <ecreased v8) and factor .###70 activity
2. 0linical findings in v8<
a. Aenorrhagia, epistaxis, easy bruisability
b. %ssociation with angiodysplasia of the right colon
/. @aboratory findings in v8<
c. #ncreased P&& and a normal P&
d. #ncreased bleeding time
<ue a platelet adhesion defect
e. %bnormal ristocetin cofactor assay
f. <ecreased v8) antigen
g. <ecreased .###7%g and .###70 activity
2. &reatment of v8<
h. <esmopressin acetate $increases v8) and .###70 activity'
i. 9ral contraceptive $estrogen has a similar action as desmopressin'
0irculating anticoagulants $inhibitors'
1. Pathogenesis
a. 0oagulation factor is destroyed by antibodies.
b. Aost common type is antibodies against factor .###70 $e.g., postpartum'.
,. 0linical findings
o Similar to those with coagulation factor deficiencies due to decreased production
2. @aboratory findings
a. Prolonged P& andEor P&&, depending on the factor deficiency
<oes not differentiate immune destruction versus decreased production
b. Aixing studies
Normal plasma is mixed with patient plasma in a test tube.
22 No correction of P& andEor P&& indicates immune destruction.
222 0orrection of P& andEor P&& indicates decreased production.
.itamin 1 deficiency
page ,5?
page ,51
1. )unction of vitamin 1
o C0arboxylates vitamin 1dependent factors ##, .##, #*, * and proteins 0 and S
,. 0auses of vitamin 1 deficiency
a. <ecreased synthesis of vitamin 1 by colonic bacteria
i. Newborns lac! bacterial coloni(ation of the bowel.
.itamin 1 levels normally decrease between days , and 4.
<anger of severe bleeding $e.g., intracerebral hemorrhage'
Newborns require an intramuscular in3ection of vitamin 1 at birth.
;reast mil! contains very little vitamin 1.
ii. Prolonged treatment with antibiotics
%ntibiotics sterili(e the bowel causing decreased production of
vitamin 1.
Aost common cause of vitamin 1 deficiency in a hospitali(ed
patient
b. <ecreased small bowel reabsorption of vitamin 1
i. Aalabsorption of fat causes malabsorption of fatsoluble vitamins.
ii. "xampleceliac disease
c. <ecreased activation of vitamin 1 by epoxide reductase in the liver
i. 8arfarin inhibits epoxide reductase.
.itamin 1dependent factors are nonfunctional.
=at poison contains warfarin.
0hildren may have exposure to warfarin from elders living in the
household.
ii. 0irrhosis
<ecreased activation of vitamin 1 and synthesis of vitamin 1
dependent coagulation factors
Prolonged P& is not corrected with intramuscular in3ection of vitamin
1.
,. 0linical findings of vitamin 1 deficiency
a. -astrointestinal bleeding
b. ;leeding into subcutaneous tissue
c. ;leeding at the time of circumcision
d. #ntracranial hemorrhage
/. &reatment of vitamin 1 deficiency
a. #f bleeding is not severe, treatment is an intramuscular in3ection of vitamin 1.
0orrects bleeding in a few hours
22 #f bleeding is severe, treatment is with fresh fro(en plasma.
i. #mmediate correction
ii. .itamin 1dependent factors are Ccarboxylated.
Hemostasis disorders in liver disease
1. Pathogenesis
a. <ecreased synthesis of coagulation factors
i. Aultiple coagulation factor deficiencies
ii. <ecreased Ccarboxylation of vitamin 1dependent factors
b. <ecreased synthesis of anticoagulants
"xamples%&###, proteins 0 and S
b. <ecreased synthesis of fibrinolytic agents $e.g., plasminogen'
c. <ecreased clearance of )<Ps and <dimers
#nterfere with platelet aggregation and polymeri(ation of fibrin
d. <ecreased clearance of tP% and decreased synthesis of :,antiplasmin
Aay produce primary fibrinolysis $see section #.'
22 @aboratory findings in liver disease
a. #ncreased P& and P&&
b. #ncreased )<Ps and <dimers
c. #ncreased bleeding time
<isseminated intravascular coagulation $<#0'
page ,51
page ,5,
1. 0auses of <#0
a. Sepsis
0ommon pathogens include E. coli $most common' and Neisseria
meningitidis
b. <isseminated malignancy
22 %cute promyelocytic leu!emia
222 Pancreatic cancer with release of procoagulants in mucin
b. 9ther causes
0rush in3uries, rattlesna!e envenomation, amniotic fluid embolism
22 Pathogenesis
a. %ctivation of the coagulation cascade
<ue to release of tissue thromboplastin andEor endothelial cell in3ury
b. )ibrin thrombi develop in the microcirculation.
22 &hrombi obstruct blood flow.
222 &hrombi consume coagulation factors $#, ##, ., .###' and trap platelets.
b. %ctivation of the fibrinolytic system
Secondary fibrinolysis due to activation of plasminogen by factor *##
22 0linical findings in <#0
a. &hrombohemorrhagic disorder
22 #schemia from occlusive fibrin thrombi
222 ;leeding from anticoagulation
)actors #, ##, ., and .### are consumed in the fibrin thrombi
c. Shoc! due to blood loss
d. <iffuse oo(ing of blood from all brea!s in the s!in and mucous membranes
e. Petechiae and ecchymoses
,. @aboratory findings in <#0
a. 0oagulation abnormalities
22 #ncreased P& and P&&
222 <ecreased fibrinogen
b. Platelet abnormalities
22 &hrombocytopenia
222 #ncreased bleeding time
c. )ibrinolysis abnormalities
Presence of )<Ps and <dimers
b. Normocytic anemia with schistocytes and reticulocytosis
=;0s are damaged by fibrin thrombi $microangiopathic hemolytic anemia'.
22 &reatment
a. &reating the underlying disease is most important.
b. &ransfuse blood components
22 )resh fro(en plasma for multiple coagulation factor deficiencies
222 Pac!ed =;0s for anemia
2222 Platelet concentrates for thrombocytopenia
!ibrinolytic Disorders
Primary fibrinolysis
page ,5,
page ,5/
1. 0auses
a. 9pen heart surgery
0ardiopulmonary bypass causes a decrease in :,antiplasmin and increase
in tP%.
b. =adical prostatectomy
0auses increased release of uro!inase
c. <iffuse liver disease
0auses a decrease in the synthesis of :,antiplasmin
,. Pathogenesis
a. )<Ps interfere with platelet aggregation.
b. Plasmin degrades coagulation factors causing multiple factor deficiencies.
/. 0linical findings
o Severe bleeding
2. @aboratory findings
a. #ncreased P& and P&&
<ue to multiple factor deficiencies
b. #ncreased bleeding time
<ue to interference with platelet aggregation
c. Positive test for )<Ps
d. Negative <dimer assay
No fibrin thrombi are present.
e. Normal platelet count
Primary fibrinolysis
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1. 0auses
a. 9pen heart surgery
0ardiopulmonary bypass causes a decrease in :,antiplasmin and increase
in tP%.
b. =adical prostatectomy
0auses increased release of uro!inase
c. <iffuse liver disease
0auses a decrease in the synthesis of :,antiplasmin
,. Pathogenesis
a. )<Ps interfere with platelet aggregation.
b. Plasmin degrades coagulation factors causing multiple factor deficiencies.
/. 0linical findings
o Severe bleeding
2. @aboratory findings
a. #ncreased P& and P&&
<ue to multiple factor deficiencies
b. #ncreased bleeding time
<ue to interference with platelet aggregation
c. Positive test for )<Ps
d. Negative <dimer assay
No fibrin thrombi are present.
e. Normal platelet count
Secondary fibrinolysis
1. 0ompensatory reaction in the presence of intravascular coagulation
2. #ncrease in both )<Ps and <dimers
"ummary of #aboratory Test $esults in Hemostasis Disorders
Table 14-%. #aboratory !indings in Common Hemostasis Disorders
Disorder or Condition Platelet Count Bleeding Time PT PTT
&hrombocytopenia #&P, &&P, HDS Normal Normal
.on 8illebrand disease Normal Normal
Hemophilia % Normal Normal Normal
<#0
Primary fibrinolysis Normal
%spirin or NS%#< use Normal Normal Normal
8arfarin or heparin use Normal Normal
<#0, disseminated intravascular coagulation+ HDS+ hemolytic uremic syndrome+ #&P, idiopathic thrombocytopenic purpura+
NS%#<, nonsteroidal antiinflammatory drug+ P&, prothrombin time+ P&&, partial thromboplastin time+ &&P, thrombotic
thrombocytopenic purpura.
Thrombosis "yndromes
%cquired thrombosis syndromes
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1. %ntiphospholipid syndrome $%P@S'
a. "pidemiology
%ssociations include S@" and H#.
b. Pathogenesis
22 Presence of antiphospholipid antibodies $%P%s'
<irected against phospholipids bound to plasma proteins
222 %P%s include anticardiolipin antibody and lupus anticoagulant.
%nticardiolipin antibody reacts with the cardiolipin reagent in the
rapid plasma reagin test for syphilis.
b. 0linical findings in %P@S
22 Produce arterial and venous thrombosis syndromes
222 =epeated abortions due to thrombosis of placental bed vessels
2222 Stro!es, thromboembolism
,. 9ther acquired causes of thrombosis
a. Postoperative state with stasis of blood flow
b. Aalignancy
22 #ncrease in coagulation factors
222 &hrombocytosis
2222 =elease of procoagulants from tumors, particularly pancreatic cancers
c. )olate or vitamin ;1, deficiency
<ue to increased plasma homocysteine levels
b. 9ral contraceptives
"strogen increases the synthesis of coagulation factors and decreases %&###
c. Hyperviscosity
22 Polycythemia syndromes
222 8aldenstrLmFs macroglobulinemia
%cquired thrombosis syndromes
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1. %ntiphospholipid syndrome $%P@S'
a. "pidemiology
%ssociations include S@" and H#.
b. Pathogenesis
22 Presence of antiphospholipid antibodies $%P%s'
<irected against phospholipids bound to plasma proteins
222 %P%s include anticardiolipin antibody and lupus anticoagulant.
%nticardiolipin antibody reacts with the cardiolipin reagent in the
rapid plasma reagin test for syphilis.
b. 0linical findings in %P@S
22 Produce arterial and venous thrombosis syndromes
222 =epeated abortions due to thrombosis of placental bed vessels
2222 Stro!es, thromboembolism
,. 9ther acquired causes of thrombosis
a. Postoperative state with stasis of blood flow
b. Aalignancy
22 #ncrease in coagulation factors
222 &hrombocytosis
2222 =elease of procoagulants from tumors, particularly pancreatic cancers
c. )olate or vitamin ;1, deficiency
<ue to increased plasma homocysteine levels
b. 9ral contraceptives
"strogen increases the synthesis of coagulation factors and decreases %&###
c. Hyperviscosity
22 Polycythemia syndromes
222 8aldenstrLmFs macroglobulinemia
Hereditary thrombosis syndromes
&here is a potential for hetero(ygote carriers of protein 0 deficiency to develop
hemorrhagic s!in necrosis when placed on warfarin. Hetero(ygote carriers have
4?I protein 0 activity. Protein 0 has a short halflife $B hours'. 8hen
patients are placed on warfarin, protein 0 activity falls to (ero activity in B hours,
causing a hypercoagulable state due to increased activity of factors . and .###.
&his causes cutaneous vessel thrombosis and concomitant s!in necrosis.
1. "pidemiology
a. %utosomal dominant syndromes
b. <eep venous thrombosis and pulmonary emboli occur at an early age.
c. .enous thromboses often occur in unusual places.
"xampleshepatic vein, dural sinus
,. )actor .@eiden
a. Aost common hereditary thrombosis syndrome.
b. Autant form of factor . cannot be degraded by protein 0 and protein S.
/. %ntithrombin ### $%&###' deficiency
a. )unctions of %&###
22 %ctivity is enhanced by heparin.
222 Neutrali(es serine proteases $e.g., factors *##, *#, #*, *, ##, thrombin'
b. No prolongation of P&& after in3ecting a standard dose of heparin
c. &reatment
22 #nfuse a greater dose of heparin than normal
P&& eventually increases due to enhancement of whatever %&### is
present.
222 Send the patient home on warfarin.
,. Proteins 0 and S deficiency
a. Pathogenesis
0annot inactivate factors . and .###
b. &reatment
22 ;egin with heparin and a very low dose of warfarin to reduce the ris! for
developing hemorrhagic s!in necrosis.
222 Send the patient home on warfarin.